1. Antimicrobial Drugs Fahareen-Binta-Mosharraf MNS 1

2. Antimicrobial Drugs  ChemotherapyThe use of drugs to treat a disease  Antimicrobial drugsInterfere with the growth of microbes within a host  AntibioticSubstance produced by a microbe that, in small amounts, inhibits another microbe  Selective toxicityA drug that kills harmful microbes without damaging the host 2

3. 3 Principles of Antimicrobial Therapy  Administer to an infected person a drug that destroys the infective agent without harming the host’s cells.  Antimicrobial drugs are produced naturally or synthetically.

4. 4

5. Basic Terminology  An antimicrobial is a chemical substance that has the capacity, in diluted solutions, to kill (biocidal activity) or inhibit the growth (biostatic activity) of microbes  The goal of antimicrobial treatment is to render the microbe helpless (either by killing them or inhibiting their replication) and not to hurt the animal being treated  Antimicrobials can be classified as:  Antibiotics  Antifungals  Antivirals  Antiprotozoals  Antiparasitics 5

6. Antibiotics  Antibiotics work only on bacteria and are described by their spectrum of action (range of bacteria for which the agent is effective)  Narrow-spectrum antibiotics work only on either gram-positive or gram-negative bacteria (not both)  Broad-spectrum antibiotics work on both gram-positive and gram-negative bacteria (but not necessarily all)  Antibiotics can be classified as bactericidal or bacteriostatic  Bactericidals kill the bacteria  Bacteriostatics inhibit the growth or replication of bacteria 6

7. 7 Origins of Antibiotic Drugs  Antibiotics are common metabolic products of aerobic spore-forming bacteria and fungi.  bacteria in genera Streptomyces and Bacillus  molds in genera Penicillium and Cephalosporium  By inhibiting the other microbes in the same habitat, antibiotic producers have less competition for nutrients and space.

8. Table 20.1 8

9. Sources  Microorganisms: polymyxin are obtained from some Bacillus species  Synthesis: Chloramphenicol is now usually produced by a synthetic process  Semisynthesis: This means that part of the molecule is produced by a fermentation process using the appropriate microorganism and the product is then further modified by a chemical process. Penicillins and cephalosporins 9

10. Table 20.2 10

11. How Do Antibiotics Work?  Antibiotics work by a variety of mechanisms:  Inhibition of cell wall synthesis  Damage to the cell membrane  Inhibition of protein synthesis  Interference with metabolism  Impairment of nucleic acids 11

12. The Action of Antimicrobial Drugs Figure 20.2 12

13. Inhibition of cell wall synthesis 13

14. Classes of Antibiotics: β-Lactam antibiotics  Beta-lactam antimicrobials - all contain a highly reactive 3 carbon, 1 nitrogen ring  Greater than ½ of all antimicrobic drugs are beta- lactams.  Mode of action: Primary mode of action is to interfere with cell wall synthesis  Penicillins and cephalosporins most prominent beta-lactams 14

15. 15

16. 16 Mode of Action  Most bacterial cell walls contain peptidoglycan.  Penicillins and cephalosporins block synthesis of peptidoglycan, causing the cell wall to lyse.  Active on young, growing cells  Penicillins do not penetrate the outer membrane and are less effective against Gram-negative bacteria.  Broad spectrum penicillins and cephalosporins can cross the cell walls of Gram-negative bacteria.

17. 17

18. Inhibits peptide bridge formation between glycan molecules This causes the cell wall to develop weak points at the growth sites and become fragile 18

19. Penicillins  Have beta-lactam structure that interferes with bacterial cell wall synthesis  Spectrum of activity depends on the type of penicillin

20.  Natural penicillins:  Those produced by fermentation of moulds such as Penicillium notatum and P. chrysogenum  Penicillin G and V are narrow-spectrum gram-positive antibiotics Penicillin G is given parenterally Penicillin V is given orally 20

21.  Semisynthetic penicillins  Broader-spectrum penicillins are semi-synthetic Examples include amoxicillin, ampicillin, carbenicillin, ticarcillin, and methicillin 21

22. Penicillins Figure 20.6 22

23. 23 Cephalosporins  Account for majority of all antibiotics administered  Isolated from Cephalosporium acremonium mold  Synthetically altered beta-lactam structure  Relatively broad-spectrum, resistant to most penicillinases, & cause fewer allergic reactions  Some are given orally; many must be administered parenterally.  Generic names have root – cef, ceph, or kef.

24.  Cephalosporins  2 nd, 3 rd, and 4 th generations more effective against gram- negatives  each group more effective against Gram-negatives than the one before with improved dosing schedule and fewer side effects Figure 20.9 24

25. 25 Cephalosporins  4 generations exist:  first generation – cephalothin, cefazolin – most effective against Gram-positive cocci and few Gram-negative  second generation – cefaclor, cefonacid – more effective against Gram-negative bacteria  third generation – cephalexin, ceftriaxone – broad- spectrum activity against enteric bacteria with beta- lactamases  fourth generation – cefepime – widest range; both Gram- negative and Gram-positive

26. 26

27.  Polypeptide antibiotics  Bacitracin Topical application Against gram-positives  Vancomycin Glycopeptide Important "last line" against antibiotic resistant S. aureus Non Beta-lactam Cell Wall Inhibitors 27

28. 28

29. Damage to the cell membrane 29

30. 30  A cell with a damaged membrane dies from disruption in metabolism or lysis.  These drugs have specificity for a particular microbial group, based on differences in types of lipids in their cell membranes. Mode of action  Polymyxins interact with phospholipids and cause leakage, particularly in Gram-negative bacteria.  Amphotericin B and nystatin form complexes with sterols on fungal membranes which causes leakage.

31. 31

32. Polymyxin B  Works by attacking the cell membrane of bacteria (remember that animal cells have cell membranes too)  Is a narrow-spectrum, gram-positive antibiotic Not absorbed when taken orally or applied topically Used as an ointment or wet dressing 32

33.  Alternation of bacterial cell membranes  Polymyxins (E)  Mainly active against gr-ve “P. aeruginosa”  Alteration of fungal cell membranes  Amphotericin B “high affinity for ergosterol” (polyene)  Nystatin “topically, Candida”  Azoles “act by inhibiting ergosterol synthesis” Alternation of cell membrane function 33

34. Drugs That Block Protein Synthesis Ribosomes of eukaryotes differ in size and structure from prokaryotes; antimicrobial drugs usually have a selective action against prokaryotes; can also damage the eukaryotic mitochondria 34

35. Mode of Action  Aminoglycosides: bind to 30S subunit causing it to distort and malfunction; blocks initiation of translation. Eg: Streptomycin, neomycin, gentamycin  Tetracyclines: bind to 30S subunit blocking attachment of tRNA  Macrolides and Erythromycin: bind 50S subunit and prevents continuation of protein synthesis  Chloramphenicol :Binds 50S subunit, inhibits peptide bond formation 35

36. The Action of Antimicrobial Drugs Figure 20.4 36

37.  Streptogramins Binds 50S subunit, inhibits translation  Synercid Binds 50S subunit, inhibits translation 37

38. Impairment of nucleic acids 38

39. 39 Mode of Action  May block synthesis of nucleotides, inhibit replication, or stop transcription  binds and cross-links the double helix  drugs that are analogs of purines and pyrimidines insert in nucleic acid, preventing replication.

40. Nucleoside and Nucleotide Analogs Figure 20.16a 40

41. Nucleoside and Nucleotide Analogs Figure 20.16b, c 41

42.  Fluoroquinolones  Inhibit action of topoisomerase,DNA gyrase  Examples include Ciprofloxacin and ofloxacin  Urinary tract infections  Rifamycins  Block prokaryotic RNA polymerase  Primarily used to treat tuberculosis and preventing meningitis after exposure to N. meningitidis 42

43. 43

44. Interference with metabolism 44

45. Mode of Action  Competitive inhibition – drug competes with normal substrate for enzyme’s active site  Synergistic effect – an additive effect, achieved by multiple drugs working together, requiring a lower dose of each 45

46. Competitive Inhibitors 46

47.  Sulfonamides (Sulfa drugs) Inhibit folic acid synthesis Most are synthetic Broad spectrum Competitive inhibitor Figure 5.7 47

48. 48

49. Figure 20.13 P-aminobenzoic acid 49

50. 50 Agents to Treat Fungal Infections  Fungal cells are eucaryotic; a drug that is toxic to fungal cells also toxic to human cells  Five antifungal drug groups:  macrolide polyene mimic lipids, most versatile and effective  griseofulvin – stubborn cases of dermatophyte infections,  synthetic azoles – broad-spectrum  flucytosine – analog of cytosine  echinocandins – damage cell walls

51. 51

52. 52 Antiparasitic Chemotherapy  Antimalarial drugs – quinine, chloroquinine, primaquine, mefloquine  Antiprotozoan drugs - sulfonamides, tetracyclines  Antihelminthic drugs – mebendazole-broad-spectrum – inhibit function of microtubules, interferes with glucose utilization and disables them

53. Antiviral Agents  Viruses are intracellular invaders that alter the host cell’s metabolic pathways  Selective toxicity is almost impossible due to obligate intracellular parasitic nature of viruses  Antiviral drugs act by preventing viral penetration of the host cell or by inhibiting the virus’s production of RNA or DNA 53

54. Mode of Action  Block penetration into host cell  Block transcription or translation of viral genetic material  nucleotide analogs acyclovir – a guanine analog AZT – thymine analog - HIV  Prevent maturation of viral particles  protease inhibitors – HIV 54

55. Interferons  Human-based glycoprotein produced primarily by leukocytes  Cells infected by a virus often produce interferon, which inhibits further spread of the infection  Alpha-interferon- drug for treatment of viral hepatitis infections 55

56.  Synergism occurs when the effect of two drugs together is greater than the effect of either alone. Eg. penicillin and streptomycin in the treatment of bacterial endocarditis. Damage to bacterial cell walls by penicillin makes it easier for streptomycin to enter  Indifference occurs when the effect of two drugs together is almost the same as the effect of either alone. Effects of Combinations of Drugs 56

57.  Antagonism occurs when the effect of two drugs together is less than the effect of either alone  For example, the simultaneous use of penicillin and tetracycline is often less effective than when wither drugs is used alone. By stopping the growth of the bacteria, the bacteriostatic drug tetracycline interferes with the action of penicillin, which requires bacterial growth. 57

58. Adverse Effects 1. Allergic Reactions: some people develop hypersensitivities to antimicrobials 2. Toxic Effects: some antimicrobials toxic at high concentrations or cause adverse effects 3. Suppression of normal flora: when normal flora killed, other pathogens may be able to grow to high numbers- Superinfection 58

59. 59

60. Resistance to Antimicrobials  Some microorganisms inherently resistant to effects of a particular drug  Other previously sensitive microorganisms can develop resistance through spontaneous mutations or acquisition of new genes  Occurs when bacteria change in some way that reduces or eliminates the effectiveness of the agent used to cure or prevent the infection  Can develop through bacterial mutation, bacteria acquiring genes that code for resistance, or other means 60

61. Mechanisms of Antibiotic Resistance  Enzymatic destruction of drug  Some organisms produce enzymes that chemically modify drug Penicillinase breaks β -lactam ring of penicillin antibiotics  Alteration of drug's target site  Minor structural changes in antibiotic target can prevent binding Changes in ribosomal RNA prevent macrolids from binding to ribosomal subunits 61

62. Mechanisms of Antibiotic Resistance  Prevention of penetration of drug  Alterations in porin proteins decrease permeability of cells Prevents certain drugs from entering  Rapid ejection of the drug  Some organisms produce efflux pumps Increases overall capacity of organism to eliminate drug o Enables organism to resist higher concentrations of drug o Tetracycline resistance 62

63. 63